The present invention relates to compounds and pharmaceutical compositions having central nervous system (CNS) activity which are useful in the treatment of epilepsy and other CNS disorders. More specifically, the compounds of this invention can be characterized as protected amino acid derivatives of the formula: ##STR2## or the N-oxides thereof or pharmaceutically acceptable salts thereof wherein
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, loweralkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; PA1 R.sub.1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group and PA1 R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, SO.sub.3.sup.- or Z--Y wherein R.sub.2 and R.sub.3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; PA1 Z is O, S,S(O).sub.a, NR.sub.4, PR.sub.4 or a chemical bond; PA1 R.sub.7 is R.sub.6 or COOR.sub.8 or COR.sub.8 PA1 R.sub.8 is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and PA1 A and Q are independently O or S, M is an alkylene chain containing up to 6 carbon atoms or a chemical bond; PA1 n is 1-4 and PA1 a is 1-3. PA1 A, Z, L and J are independently CH, or a heteroatom selected from the group consisting of N, O, S, and PA1 G is CH, or a heteroatom selected from the group consisting of N, O and S, PA1 but when n is O, G is CH, or a heterocyclic selected from the group consisting of NH, O and S with the proviso that at most two of A, E, L, J and G are heteroatoms. PA1 R.sub.2 and R.sub.3, independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, lower alkyl heterocyclic, each unsubstituted or substituted with at least one substituent; halogen or a heteroatom containing oxygen, nitrogen, sulfur or phosphorous substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; and PA1 n is 1 to 4. PA1 R.sub.1 is H or lower alkyl, unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; PA1 R.sub.2 and R.sub.3, independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron donating substituent, halogen or a heteroatom containing oxygen, nitrogen, sulfur or phosphorous substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; and PA1 n is 1 to 4. PA1 R.sub.1 is H or lower alkyl which may be unsubstituted or substituted with at least one halo, nitro, acyl, carboxamide, cyano, sulfonyl, sulfoxide (sulfinyl), heterocyclic, guanidine, quaternary ammonium, hydroxy, lower alkoxy, amino, phenoxy, sulfide, or disulfide; PA1 R.sub.2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; halogen or a heteroatom consisting of oxygen, nitrogen, sulfur or phosphorous, said heteroatom being substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; PA1 R.sub.3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; halogen or a heteroatom consisting of oxygen, nitrogen, sulfur, or phosphorous said heteroatom being substituted with hydrogen, lower alkyl or aryl, said lower alkyl of aryl groups being substituted or unsubstituted; PA1 and n is 1 to 4; PA1 R.sub.1 is hydrogen or lower alkyl, unsubstituted or substituted with an electron donating group or an electron withdrawing group and PA1 R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, or Z--Y wherein R.sub.2 and R.sub.3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; PA1 Z is O, S,S(O).sub.a, NR.sub.4, PR.sub.4 or a chemical bond; PA1 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, or halo and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond, or PA1 ZY taken together is NR.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, ONR.sub.4 R.sub.7, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 R.sub.7, NR.sub.4 SR.sub.7, SPR.sub.4 R.sub.5 or PR.sub.4 SR.sub.7, NR.sub.4 PR.sub.5 R.sub.6 or PR.sub.4 NR.sub.5 R.sub.7, ##STR13## R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5 and R.sub.6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and PA1 R.sub.7 is R.sub.6 or COOR.sub.8 or COR.sub.8, R.sub.8 is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or lower alkyl groups may be unsubstituted or substituted with an electron withdrawing or electron donating group, PA1 n is 1-4 and PA1 a is 1-3. PA1 R.sub.1 is hydrogen or lower alkyl which is unsubstituted or substituted with at least one electron withdrawing group or one electron donating group, PA1 R.sub.2 and R.sub.3 are independently hydrogen, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, Z--Y or a heterocyclic group which may be unsubstituted or substituted with at least one electron withdrawing or one electron donating group, with the proviso that R.sup.2 and R.sup.3 cannot both be hydrogen; PA1 Z is O, S, NR.sub.4, PR.sub.4 or a chemical bond; PA1 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl or halo, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond; or PA1 ZY taken together is NR.sub.4 NR.sub.5 R.sub.6, NR.sub.4 OR.sub.5, ONR.sub.4 R.sub.5, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 R.sub.5, NR.sub.4 SR.sub.5, SPR.sub.4 R.sub.5, or PR.sub.4 SR.sub.5, NR.sub.4 PR.sub.5 R.sub.6 or PR.sub.4 NR.sub.5 R.sub.6, PA1 R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5 and R.sub.6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; PA1 n is 1-4. PA1 R.sub.17 =lower alkyl, aryl, aryl lower alkyl, ##STR18## wherein R.sub.3 =aryl, heteroaromatic and R.sub.17 is as defined hereinabove. PA1 M+=metal cation (i.e., Na.sup.+, K.sup.+)
Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, cycloalkyl, cycloalkyl lower alkyl and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided Z is a chemical bond only, when Y is halo, or
ZY taken together is NR.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, ONR.sub.4 R.sub.7, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 R.sub.7, NR.sub.4 SR.sub.7, SPR.sub.4 R.sub.5, PR.sub.4 SR.sub.7, NR.sub.4 PR.sub.5 R.sub.6 PR.sub.4 NR.sub.5 R.sub.7, ##STR3## R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, R.sub.5 and R.sub.6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and
The predominant application of anticonvulsant drugs is the control and prevention of seizures associated with epilepsy or related central nervous system disorders. Epilepsy refers to many types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain; the two main generalized seizures are petit mal, which is associated with myoclonic jerks, akinetic seizures, transient loss of consciousness, but without convulsion; and grand mal which manifests in a continuous series of seizures and convulsions with loss of consciousness.
The mainstay of treatment for such disorders has been the long-term and consistent administration of anticonvulsant drugs. Most drugs in use are weak acids that, presumably, exert their action on neurons, glial cells or both of the central nervous system. The majority of these compounds are characterized by the presence of at least one amide unit and one or more benzene rings that are present as a phenyl group or part of a cyclic system.
Much attention has been focused upon the development of anticonvulsant drugs and today many such drugs are well known. For example, the hydantions, such as phenytoin, are useful in the control of generalized seizures and all forms of partial seizures. The oxazolidinediones, such as trimethadione and paramethadione, are used in the treatment of nonconvulsive seizures. Phenacemide, a phenylacetylurea, is one of the most well known anticonvulsants employed today, while much attention has recently been dedicated to the investigation of the diazepines and piperazines. For example, U.S. Pat. Nos. 4,002,764 and 4,178,378 to Allgeier, et al. disclose esterified diazepine derivatives useful in the treatment of epilepsy and other nervous disorders. U.S. Pat. No. 3,887,543 to Nakanishi, et al. describes a thieno[2,3-e][1,4]diazepine compound also having anticonvulsant activity and other depressant activity. U.S. Pat. No. 4,209,516 to Heckendorn, et al. relates to triazole derivatives which exhibit anticonvulsant activity and are useful in the treatment of epilepsy and conditions of tension and agitation. U.S. Pat. No. 4,322,974 to Fish, et al. discloses a pharmaceutical formulation containing an aliphatic amino acid compound in which the carboxylic acid and primary amine are separated by three or four units. Administration of these compounds in an acid pH range are useful in the treatment of convulsion disorders and also possess anxiolytic and sedative properties.
Unfortunately, despite the many available pharmacotherapeutic agents, a significant percentage of the population with epilepsy or related disorders are poorly managed. Moreover, none of the drugs presently available are capable of achieving total seizure control and most have disturbing side-effects. Clearly, current therapy has failed to "seize control" of these debilitating diseases.
It is therefore one object of the present invention to provide novel compounds exhibiting CNS activity, particularly anticonvulsant activity.
Another object of this invention is to provide pharmaceutical compositions useful in the treatment of epilepsy and other CNS disorders.
A further object of this invention is to provide a method of treating epilepsy and related convulsant disorders.
These and other objects are accomplished herein by providing compounds of the following general formula: ##STR4## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n, Z, Y, A and Q are as defined hereinabove.
The present invention contemplates employing the compounds of Formula I in compositions of pharmaceutically acceptable dosage forms. Where the appropriate substituents are employed, the present invention also includes pharmaceutically acceptable addition salts. Moreover, the administration of an effective amount of the present compounds, in their pharmaceutically acceptable forms or the addition salts thereof, can provide an excellent regime for the treatment of epilepsy, nervous anxiety, psychosis, insomnia and other related central nervous disorders.
The alkyl groups when used alone or in combination with other groups, are lower alkyl containing from 1 to 6 carbon atoms and may be straight chain or branched. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl, and the like.
The aryl lower alkyl groups include, for example, benzyl, phenethyl, phenpropyl, phenisopropyl, phenbutyl, and the like, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, and the like.
The term aryl, when used along or in combination, refers to an aromatic group which contains from 6 up to 18 ring carbon atoms and up to a total of 25 carbon atoms and includes the polynuclear aromatics. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. Polynuclear aromatic compound is meant to encompass bicyclic, tricyclic fused aromatic ring system containing from 10-18 ring carbon atoms and up to a total of 25 carbon atoms. The aryl group includes phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. The aryl group also includes groups like ferrocenyl.
Lower alkenyl is an alkenyl group containing from 2 to 6 carbon atoms and at least one double bond. These groups may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E-)-4-methyl-2-pentenyl, pentadienyl, e.g., 1,3 or 2,4-pentadienyl, and the like.
The term alkynyl include alkyene substituents containing 2 to 6 carbon atoms and may be straight chained as well as branched. It includes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.
The term cycloalkyl when used alone or in combination is a cycloalkyl group containing from 3 to 18 ring carbon atoms and up to a total of 25 carbon atoms. The cycloalkyl groups may be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. The cycloalkyl may be completely saturated or partially saturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl, adamantyl, and the like. Cycloalkyl includes the cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.
The term "electron-withdrawing and electron donating" refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if the hydrogen atom occupied the same position in the molecule. These terms are well understood by one skilled in the art and are discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York N.Y., pp. 16-18 (1985) and the discussion therein is incorporated herein by reference. Electron withdrawing groups include halo, including bromo, fluoro, chloro, iodo and the like; nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl lower alkanoyl, carbalkoxy and the like. Electron donating groups include such groups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl, and the like; amino, lower alkylamino, di(loweralkyl)amino, aryloxy such as phenoxy, mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) and the like. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.
The term halo includes fluoro, chloro, bromo, iodo and the like.
The term acyl includes lower alkanoyl.
As employed herein, the heterocyclic substituent contains at least one sulfur, nitrogen or oxygen, but also may include one or several of said atoms. The heterocyclic substituents contemplated by the present invention include heteroaromatics and saturated and partially saturated heterocyclic compounds. These heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. They may contain up to 18 ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25 carbon atoms. The heterocyclics are also intended to include the so-called benzoheterocycles. Representative heterocyclics include furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxides of the nitrogen containing heterocycles, such as the nitric oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like. The preferred heterocyclic are thienyl, furyl, pyrroly, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, merpholinyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, pyrazolyl or pyridazinyl. The preferred heterocyclic is a 5 or 6-membered heterocyclic compound. The especially preferred heterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, epoxy, pyrimidinyl, or pyridazinyl. The most preferred heterocyclics are furyl, pyrazolyl, pyrrolyl and pyridyl.
The preferred compounds are those wherein n is 1, but di, tri and tetrapeptides are also contemplated to be within the scope of the claims.
The preferred values of R is aryl lower alkyl, especially benzyl, and the preferred R.sub.1 is H or lower alkyl. The most preferred R.sub.1 group is methyl.
The most preferred electron donating substituent and electron withdrawing substituent are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio; and alkyldithio. The term "sulfide" encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkyldithio. These preferred substituents may be substituted on any one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 or R.sub.6, R.sub.7 or R.sub.8 as defined herein.
The ZY groups representative of R.sub.2 and R.sub.3 include hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino; alkylamino, such as methylamino, ethylamino; arylamino, such as anilino; lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt, hydrazino, alkylhydrazino and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino (--NH--OH), lower alkoxy amino [(NHOR.sub.18) wherein R.sub.18 is lower alkyl], N-lower alkylhydroxyl amino [(NCR.sub.18)OH wherein R.sub.18 is lower alkyl], N-lower alkyl-O-lower alkyl hydroxyamino, i.e., [N(R.sub.18)OR.sub.19 wherein R.sub.18 and R.sub.19 are independently lower alkyl] and o-hydroxylamino (--O--NH.sub.2); alkylamido such as acetamido, trifluoroacetamido, lower alkoxyamino, (e.g. NH(OCH.sub.3); and heterocyclicamino, such as pyrazoylamino.
Furthermore, in still another embodiment Z may be O, S, NR.sub.4 or PR.sub.4 and Y may be hydrogen, lower alkyl or aryl and R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined hereinabove.
In a still further embodiment, ZY may be ##STR5## and R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined hereinabove.
When R.sub.2 or R.sub.3 is heterocyclic, the preferred heterocyclics are furyl, tetrahydrofuryl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl or epoxy. The most preferred heterocyclic is furyl, pyridyl, pyrazoyl and pyrrolyl.
The preferred heterocyclic groups representative of R.sub.2 and R.sub.3 have the formula ##STR6## or those corresponding partially or fully saturated form thereof wherein n is 0 or 1
If the ring depicted hereinabove contains a nitrogen ring atom, then the N-oxide forms are also contemplated to be within the scope of the invention.
When R.sub.2 or R.sub.3 is a heterocyclic of the above formula, it may be bonded to the main chain by a ring carbon atom. When n is O, R.sub.2 or R.sub.3 may additionally be bonded to the main chain by a nitrogen ring atom.
R.sub.2 or R.sub.3 may independently also be SO.sub.3.sup.-, or SO.sub.2.sup.-.
Furthermore, ZY may also be ##STR7##
When R.sub.2 is alkenyl the alkenyl group is a lower alkenyl group having 1-6 carbon atoms. The alkenyl group may be substituted with an electron donating group and more preferably with an electron withdrawing group, such as COOH.
As indicated hereinabove, Q and A may be O or S; in other words, the main chain may contain only C.dbd.O, only --C.dbd.S or combinations thereof. All such permutations are contemplated herein. It is preferred that the compounds of the present invention contain no more than 2 C.dbd.S moieties, it is even more preferred that the compounds of the present invention contain no more than 1 C.dbd.S moiety. The most preferred embodiment are when A and Q are both oxygen.
An embodiment of the present application is one in which the compounds are of Formula I wherein R is lower cycloalkyl or lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group and R.sub.1, R.sub.2, R.sub.3, Z, Y or ZY taken together, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined herein.
Another embodiment of the present invention include compounds of Formula I wherein R.sub.1 is lower cycloalkyl or lower cycloalkyl lower alkyl and R.sub.1 may be unsubstituted or substituted with an electron donating group or electron withdrawing group and R.sub.1, R.sub.2, R.sub.3, Z, Y, or ZY taken together, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 n and a are as defined hereinabove.
Another embodiment of the present invention includes compounds of Formula I wherein R.sub.2 is lower cycloalkyl or lower cycloalkyl lower alkyl and R.sub.2 may be unsubstituted or substituted with an electron donating group or electron withdrawing group, and R, R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and a are as defined hereinabove.
Still another embodiment of the present invention include compounds of Formula I wherein R.sub.3 is lower cycloalkyl or lower cycloalkyl lower alkyl and R.sub.3 may be unsubstituted or substituted with an electron donating or electron withdrawing group and R, R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined hereinabove.
A further embodiment of the present invention include compounds of Formula I wherein Z is S(O).sub.a and R, R.sub.1, R.sub.2, R.sub.3, Y, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined herein.
It is preferred that one of R.sub.2 and R.sub.3 is hydrogen.
In a preferred embodiment, one of R.sub.2 and R.sub.3 is hydrogen and that the other is heterocyclic. It is preferred that one of R.sub.2 and R.sub.3 is a heterocyclic having Formula XI. The preferred heterocyclics include furyl, thienyl, benzothienyl, benzofuryl, oxazolyl, thiazolyl, isoxazolyl, indolyl, pyrazolyl, isoxazolidinyl, benzothienyl, benzofuryl, morpholinyl, indolyl, pyrrolyl, furfuryl, and methylpyrrolyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl or pyridazinyl, pyrazolyl, or epoxy. In another preferred embodiment, one of R.sub.2 and R.sub.3 is alkyl (e.g. methylisopropyl), aryl (e.g., phenyl), 2-thiomethylethyl, lower alkoxy (e.g., ethoxy, methoxy), anilino, propenyl, alkylamino (e.g., ethylamino or methylamino). In another preferred embodiment, one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic lower alkyl, lower alkenyl, amino, lower alkoxy amino, N-lower alkylhydroxyamino, lower alkoxyamino, N-lower alkyl-O-lower alkylhydroxyamino or aralkoxycarbonylhydrazino.
Preferred compounds of the present invention have the following general formula: ##STR8## wherein R.sub.1 is H or lower alkyl, R.sub.2 and R.sub.3 are as defined above and A is hydrogen or an electron donating group or electron-withdrawing group and m is 0-5. It is preferred that A is hydrogen (i.e., m=0). However, values of m equalling 1, 2 or 3 are also preferred.
Preferred embodiments include compounds of Formula I ##STR9## wherein R and R.sub.1, independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, lower alkyl heterocyclic, each unsubstituted or substituted with at least one substituent;
Another preferred embodiment is a compound having Formula I ##STR10## wherein R is aryl, aryl lower alkyl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic or lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent;
Another preferred embodiment of the present invention is a compound of Formula I ##STR11## wherein R is aryl lower alkyl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic or lower alkyl polynuclear aromatic, each of which may be unsubstituted or substituted with at least one halo, nitro, acyl, carboxyl, carboalkoxy, carboxamide, cyano, sulfonyl, sulfoxide (sulfinyl), heterocyclic, guanidine, quaternary ammonium hydroxy, alkoxy, alkyl, amino, phenoxy, mercapto, sulfide or disulfide;
Another preferred embodiment is a compound of Formula I ##STR12## wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl and R is unsubstituted or is substituted with at least one electron withdrawing group, or electron donating group;
Another class of preferred compounds of the Formula I have the formula ##STR14## wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic alkyl which is unsubstituted or substituted with at least one electron withdrawing group or at least one electron donating group;
Of this preferred group, it is especially preferred that n is 1.
The preferred compounds are those in which R is aryl, aryl lower alkyl, heterocyclic, or heterocyclic lower alkyl, R.sub.1 is hydrogen or lower alkyl, R.sub.2 and R.sub.3 are independently hydrogen, heterocyclic, lower alkyl, aryl, lower alkoxy, lower alkenyl, amino, hydroxylamino, lower alkoxy amino, N-lower alkyl hydroxyamino, N-lower alkyl-o-lower alkyl hydroxyamino, aralkoxy carbonyl hydrazino or alkylmercapto and n is 1.
In another preferred embodiment, n is 1, R and R.sub.1 are as defined hereinabove and one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic, heterocyclic lower alkyl, aryl N-hydroxylamino, lower alkoxyamino, N-lower alkylhydroxylamino, N-lower alkyl-O-lower alkylhydroxyamino.
Another preferred embodiment is wherein n is 1, R and R.sub.1 are as defined hereinabove, one of R.sub.2 and R.sub.3 is as defined hereinabove or the other is heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, aryl, N-hydroxylamino, lower alkoxy amino, N-lower alkyl hydroxylamino, N-lower alkyl-o-lower alkyl hydroxylamino, lower alkoxy, dialkyl lower amino, lower alkylamino, aryl lower alkyloxy hydrazino, or lower alkylmercapto.
The various combination and permutations of the Markush groups of R.sub.1, R.sub.2, R.sub.3 R and n described herein are contemplated to be within the scope of the present invention. Moreover, the present invention also encompasses compounds and compositions which contain one or more elements of each of the Markush groupings in R.sub.1, R.sub.2, R.sub.3, n and R and the various combinations thereof. Thus, for example, the present invention contemplates that R.sub.1 may be one or more of the substituents listed hereinabove in combination with any and all of the substituents of R.sub.2, R.sub.3 and R with respect to each value of n.
The compounds of the present invention may contain one (1) or more asymmetric carbons and may exist in racemic and optically active forms. The configuration around each asymmetric carbon can be in either the D or L form. (It is well known in the art that the configuration around a chiral carbon atoms can also be described as R or S in the Cahn-Prelog-Ingold nomenclature system). All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers as well as racemic mixtures and mixtures of enantiomers, diastereomers or both are contemplated by the present invention.
In the principal chain, there exists asymmetry at the carbon atoms to which the groups R.sub.2 and R.sub.3 are attached as substituted. When n is 1, the compounds of the present invention is of the formula ##STR15## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, Z and Y are as defined previously. As used herein, the term configuration shall refer to the configuration around the carbon atom to which R.sub.2 and R.sub.3 are attached, even though other chiral centers may be present in the molecule. Therefore, when referring to a particular configuration, such as D or L, it is to be understood to mean the stereoisomer, including all possible enantiomers and diastereomers. The compounds of the present invention are directed to all of the optical isomers, i.e., the compounds of the present invention are either the L-stereoisomer or the D-stereoisomer. These stereoisomers may be found in mixtures of the L and D stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred.
Depending upon the substituents, the present compounds may form addition salts as well. All of these forms are contemplated to be within the scope of this invention including mixtures of the stereoisomeric forms.
The following three schemes of preparation are generally exemplary of the process which can be employed for the preparation of the present complex. Although the compounds in the schemes hereinabove contain only the ##STR16## moiety, it is just as applicable to compounds of Formula I wherein either A or Q is sulfur or both A or Q are sulfur. ##STR17## wherein
More specificically these compounds can be prepared by art-recognized procedures from known compounds or readily preparable intermediates. For instance, compounds of Formula I can be prepared by reacting amines of Formula II with an acylating derivative of a carboxylic acid of Formula III under amide forming conditions: ##STR19## wherein R, R.sub.1, R.sub.2, R.sub.3 and are as defined hereinabove and n=1.
The amide forming conditions referred to herein involve the use of known derivatives of the described acids, such as the acyl halides, (e.g., ##STR20## wherein X is Cl, Br and the like), anhydrides (e.g., ##STR21## mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazoles, and the like. It is preferred that the acylating derivative used is the anhydride, ##STR22## When alkyl esters are employed, amide bond formation can be catalyzed by metal cyanides such as sodium or potassium cyanides.
Another exemplary procedure for preparing compounds wherein at least one of R.sub.2 and R.sub.3 is aromatic or heteroaromatic is depicted in Scheme IV.
The ester (IV) is reacted with halogen and ultraviolet light in the presence of a catalyst, e.g., AIBN, to form the halo derivative (V). (V) is reacted in the presence of a Lewis acid, such as zinc chloride, with an aromatic or heteroaromatic compound to form the compound (VI). (VI) in turn is hydrolyzed and then reacted with alkylhaloformate, such as alkylchloroformate in the presence of a tertiary amine to generate the mixed N-acyl amino acid carbonic ester anhydride (VIII). This intermediate is reacted with an amine under amide forming conditions to give the compound of Formula I. Alternatively, (VI) can be reacted directly with an amine (RNH.sub.2) optionally in the presence of a metal catalyst, such as metal cyanides, e.g., potassium or sodium cyanide, under amide forming conditions to form a compound of Formula I. Alternatively, compound VIII can be prepared by an independent method and converted to VI which is then reacted with an amine, with or without catalyst to form the compound of Formula I. ##STR23## X=halogen (i.e., Cl, Br) R.sub.17 =lower alkyl, aryl, arly lower alkyl
Two additional synthetic routes may be employed for the preparation of compounds wherein R.sub.2 or R.sub.3 is Z--Y as defined hereinabove. In one scheme, for the preparation of these complexes, a substitution reaction is used: ##STR24##
In the above scheme, R.sub.9 is lower alkyl, R.sub.2 is Z--Y and Z, Y, R, R.sub.3 and R.sub.1 are as defined hereinabove.
The ether functionality on IX can be cleaved by treatment with Lewis acids, such as BBr.sub.3 in an inert solvent such as methylene chloride to form the corresponding halo (bromo) derivative. Addition of either an excess of the H--R.sub.2 or MR.sub.2 or the sequential addition of triethylamine and H--R.sub.2 to a THF mixture containing the halo derivative furnishes the desired product. For example, in the case wherein the compound of Formula IX is 2-acetamido-N-benzyl-2-ethoxy acetamide, its treatment with BBr.sub.3 in CH.sub.2 Cl.sub.2 led to the formation of the .alpha.-bromo derivative, 2-acetamido-N-benzyl-2-bromoacetamide. Addition of an excess of HR.sub.2 or the sequential addition of HR.sub.2 to a THF mixture containing the bromo adduct furnishes the desired product.
In another procedure, the product wherein R.sub.2 or R.sub.3 is Z--Y can also be prepared by substitution reaction on a quaternary ammonium derivative of the compound of Formula I as outlined below ##STR25##
In scheme VI, R, R.sub.1, R.sub.3 and R are as defined hereinabove, R.sub.2 is Z--Y and R.sub.9 and R.sub.10 are independently lower alkyl. In scheme VI, methylation of compound X with a methylation reagent, such as trimethyloxonium tetrafluoroborate provided the corresponding ammonium derivative. Subsequent treatment of the ammonium salt with HR.sub.2 furnishes the desired product. For example, methylation of 2-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide with trimethyloxonium tetrafluoroborate in nitromethane furnished the quaternary ammonium derivative, 2-acetamido-N-benzyl-(N,N,N-trimethylammonium)acetamide tetrafluoroborate in high yields. Subsequent treatment of the salt with the HR.sub.2 reagent in the methanol leads to the production of the desired product.
As in any organic reaction, solvents can be employed such as methanol, ethanol, propanol, acetone, tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, chloroform, and the like. The reaction is normally effected at or near room temperature, although temperatures from 0.degree. C. up to the reflux temperature of the reaction mixture can be employed.
As a further convenience, the amide forming reaction can be effected in the presence of a base, such as tertiary organic amine, e.g., triethylamine, pyridine, 4-methylmorpholine, picolines and the like, particularly where hydrogen halide is formed by the amide forming reaction, e.g., the reaction acyl halide and the amine of Formula II. Of course, in those reactions where hydrogen halide is produced, any of the commonly used hydrogen halide acceptors can also be used.
The exact mineral acid or Lewis acid employed in the reaction will vary depending on the given transformation, the temperature required for the conversion and the sensitivity of the reagent toward the acid in the reaction employed.
Compounds of the present invention in which Q or A is S are prepared from the corresponding compounds in which Q or A is O by art recognized techniques. For example, one reagent that can be used is Lawesson's reagent, i.e., [2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2-,4-disulfide]. This reagent is a known reagent for the thiation of such compounds as ketones, carboxamides, esters, lactones, lactams, imides, enamines, and S-substituted thioesters. Thus, this reagent can be used to transform compounds of Formula I wherein Q or A is O to compounds wherein one or both of Q or A is S. The number of ##STR26## groups in the final product is dependent upon the amount of reagent added and the number of ##STR27## groups present (i.e., the value of n) in the reactants having Formula I. For example, if n is 1, and both Q and A are oxygen, than the compounds of Formula I have two ##STR28## groups. Thus, if it is desired that both ##STR29## groups be transformed to ##STR30## then approximately equimolar amount or a slight excess of is added to compounds of Formula I. On the other hand, if only one ##STR31## group is desired in the final product, then approximately 1/2 molar equivalent of Lawesson's reagent is used.
Furthermore, it is not necessary to add the reagent at the last step of the synthesis; the reagent can be added at any stage of the syntheses outlined in Schemes I-VI hereinabove. As before, the amount of the reagent added depends upon the number of ##STR32## desired in the product, and the number of ##STR33## groups in the reactant.
Regardless of which step in the synthesis the reagent is added, the reagent and the compound of Formula I having at least one ##STR34## group or an intermediate thereof is dissolved in an inert solvent, such as THF and heated at a temperature effective to convert the ##STR35## group to ##STR36## Temperatures ranging from room temperature to the reflux temperature of the solvent can be used. In cases when n=1, it is preferred that the reaction is heated to about reflux if both Q and A are converted to S and that about room temperature be used if one of Q or A is converted to S.
The various substituents on the present new compounds, e.g., as defined in R, R.sub.1, R.sub.2 and R.sub.3 can be present in the starting compounds, added to any one of the intermediates or added after formation of the final products by the known methods of substitution or conversion reactions. For example, the nitro groups can be added to the aromatic ring by nitration and the nitro group converted to other groups, such as amino by reduction, and halo by diazotization of the amino group and replacement of the diazo group. Alkanoyl groups can be substituted onto the aryl groups by Friedel-Crafts acylation. The acyl groups can be then transformed to the corresponding alkyl groups by various methods, including the Woff-Kishner reduction and Clemmenson reduction. Amino groups can be alkylated to form mono, dialkylamino and trialkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding thioethers or ethers, respectively. Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration reactions can be employed to provide a variety of substituents throughout the molecule of the starting material, intermediates, or the final product.
In the above reactions, if the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups known in the art may be employed. Examples of many of these possible groups may be found in "Protective Groups in Organic Synthesis," by T. W. Greene, John Wiley & Sons, 1981.
Resulting mixtures of isomers can be separated in the pure isomers by methods known to one skilled in the art, e.g., by fractional distillation, crystallization and/or chromotagraphy.
The present compounds obviously exist in stereoisomeric forms and the products obtained thus can be mixtures of the isomers, which can be resolved. Optically pure functionalized amino acid derivatives can be prepared directly from the corresponding pure chiral intermediate. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g., by fractional crystallization, by selective enzymatic hydrolysis, e.g., papain digestion, or by use of a chiral stationary phase in chromotagraphy (HPLC). For a discussion of chiral stationary phases for HPLC, See, DeCamp, Chirality, 1, 2-6 (1989), which is incorporated herein by reference with the same force and effect as if fully set forth herein.
For example, a racemic mixture of any of the intermediate in any of the schemes, e.g., ##STR37## wherein R.sub.17 is H (which can be prepared according to the procedures of Schemes 1, 2, 3 or 4) is reacted with an optically active amine, RNH.sub.2, e.g., (R)(+).alpha.-methylbenzylamine to form a pair of diasteroomeric salts. Diastereomers can then be separated by recognized techniques known in the art, such as fractional recrystallization and the like.
In another method, a racemic mixture of final products or intermediates can be resolved by using enzymatic methods. Since enzymes are chiral molecules, it can be used to separate the racemic modification, since it will preferentially act on one of the compounds, without affecting the enantiomer. For example, acylase, such as acylase I, can be used to separate the racemic modification of an intermediate D,L(.+-.).alpha.-acetamido-2-furanacetic acid. It acts on the L (.+-.).alpha.-acetamido-2-furanacetic acid, but will not act on the D enantiomer. In this way, the D(-).alpha.-acetamido-2-furanacetic acid can be isolated. The intermediate can then react with the amine (RNH.sub.2) under amide forming conditions as described hereinabove to form the compound of Formula I.
The active ingredients of the therapeutic compositions and the compounds of the present invention exhibit excellent anticonvulsant activity when administered in amounts ranging from about 10 mg to about 100 mg per kilogram of body weight per day. A preferred dosage regimen for optimum results would be from about 20 mg to about 50 mg per kilogram of body weight per day, and such dosage units are employed that a total of from about 1.0 gram to about 3.0 grams of the active compound for a subject of about 70 kg of body weight are administered in a 24-hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response and is preferably administered one to three times a day in dosages of about 600 mg per administration. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that the active compound may be administered in an convenient manner such as by the oral, intraveneous (where water soluble), intramuscular or subcutaneous routes.
The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 1000 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintergrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. For example, sustained release dosage forms are contemplated wherein the active ingredient is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin.
The active compound may also be administered parenterally or intraperitoncally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin; by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain the principal active compound in amounts ranging from about 5 to about 1000 mg, with from about 250 to about 750 mg being preferred. Expressed in proportions, the active compound is generally present in from about 10 to about 750 mg/ml of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
The compounds of the present invention may be administered in combination with other anti-convulsant agents, such as phenytoin, phenbarbitol, mephenytoin, and phenacemide, and the like. This combination is likely to exhibit synergistic effects.
For a better understanding of the present invention together with other and further objects, reference is made to the following description and examples.
General Methods.
Melting points were determined with a Thomas-Hoover melting point apparatus and are uncorrected. Infrared spectra (IR) were run on a Beckman IR-4250 and Perkin-Elmer 1330 and 283 spectrophotometers and calibrated against the 1601-cm.sup.-1 band of polysytrene. Absorption values are expressed in wavenumbers (cm.sup.-1). Proton nuclear magnetic resonance (.sup.1 H NMR) spectra were recorded on Varian Associates Models T-60 and FT-80A, General Electric QE 300, and Nicolet NT-300 NMR spectrometers. Carbon nuclear magnetic resonance (.sup.13 C NMR) spectra were run on a Varian Associates Models FT-80A General Electric QE 300 and Nicolet NT-300 instrument. Chemical shifts are in parts per million (.delta. values) relative to Me.sub.4 Si, and coupling constants (J values) are in hertz. Mass spectral data were obtained at an ionizing voltage of 70 eV on a Hewlett-Packard 5930 gas chromotagraph-mass spectrometer and a Bell-Howell 21-491 spectrometer as well as at the Eli Lilly Laboratories on a Varian MAT-CH-5 spectrometer. High-resolution (EI mode) mass spectra were performed by Drs. James Hudson and John Chinn at the Department of Chemistry, University of Texas at Austin, on a CEC21-110B double-focusing magnetic-sector spectrometer at 70 eV. Elemental analyses were obtained at Spang Microanalytical Laboratories, Eagle Harbor, Mich. and at the Eli Lilly Research Laboratories.
The solvents and reactants were of the best commercial grade available and were used without further purification unless noted. All anhydrous reactions were run under nitrogen, and all glassware was dried before use. In particular, acetonitrile and triethylamine were distilled from CaH.sub.2, while dichloromethane was distilled from P.sub.2 O.sub.5. Acetic anhydride, benzaldehyde and ethyl chloroformate were fractionally distilled.
Preparation of N-Acetyl-D- and L-amino acid-N-benzylamides.
General Procedure.
The D- or L-amino acid amide (11 mmol) was dissolved in dichloromethane (15 mL) and then acetic anhydride (1.23 g, 1.40 mL, 12 mmol) was added dropwise. The solution was stirred at room temperature (18 h) and then concentrated to dryness. The residue was recrystallized from chloroform/hexane. The following examples 1-7 were prepared according to this procedure.